The long term objective of our work is the elucidation of mechanisms that regulate spontaneous production of autoantibodies important in SLE. We believe that the final understanding of the basic abnormalities responsible for autoimmunity will come only through direct study of autoantibodies, rather than general immune abnormalities. We have targeted the anti-Sm response in MRL mice, because the striking specificity of this autoantibody for the diagnosis of SLE in both humans and mice indicates that it may be intimately linked to basic immunoregulatory abnormalities. The current proposal is focused on the following questions: 1) Why do only some MRL mice produce the anti-Sm antibody? The possibilities of maternal influence, stochastic events, or cellular and humoral immunoregulation will be investigated by several approaches. 2) Why are anti-Sm antibodies relatively restricted to one (IgG2a) subclass? Our recent finding of a similar restriction in human anti-Sm antibodies reinforces our belief that this restriction reflects important immunoregulatory control mechanisms. Clonal restriction of the anti-Sm response will also be investigated by analysis of idiotypes and isoelectric focusing patterns. 3) How does the generation of anti-Sm specific B-cell precursors reflect immunoregulation of the anti-Sm response? In contrast to most autoantibody systems studied, it has only been possible to demonstrate anti-Sm specific B-cell precursors in mice already making anti-Sm antibody. This observation suggests that the production of anti-Sm antibodies requires the generation of a "forbidden clone" of B cells.